The physicochemical, pharmacokinetic and pharmacological properties of drugs and their products will often dictate how they should be used in a therapeutic situation. A drug characterized by a short biological half-life should be administered in short dosing intervals to maintain the plasma concentration levels that provide the pharmacologic action. This often reduces patient compliance and as a result leads to underdosing between the dosage intervals. An ideal oral dosage form would be a once-daily formulation able to maintain the therapeutic drug levels in the body for 24 hours, yet without the risk of any adverse reactions. The use of controlled/extending release dosage forms in drug therapy has been increasing in recent years with a concomitant tendency toward once-a-day dosing formulations. Listings of controlled/extended release products and their design can be rather extensive (L. Krowczynski, Extended Release Dosage Forms, CRC-Press Inc., USA, 1987, ISBN 0-8493-4307-0).
Among formulations devised to avoid limitations due to a short biological half-life (rapid metabolism/elimination) have been technically developed dosage forms which provide release of the desired drug over an extended period of time, thereby slowing the drug's absorption. Over the past two decades considerable progress has been made in developing controlled/extended release technologies for drug compounds. The design of various controlled/extended release formulations and their technologies are known in the art (L. Krowczynski, Extended Release Dosage Forms, CRC-Press Inc., USA, 1987, ISBN 0-8493-4307-0).
Some important advantages of such delivery systems are:
reduction of the frequency of dosing (with a concomitant increase in patient compliance); PA1 maintenance of therapeutic plasma drug levels for a longer period of time than would be indicated by the drug's biological half-life; PA1 reduction of undesired adverse reactions/toxicity (by suppresion of the initial high plasma concentration peak); PA1 reduction of the amount of drug required for treatment (also provided by reducing the very high initial plasma concentrations). PA1 a slower in vivo absorption of buspirone and hence lower plasma peak values which reduce the occurrence of undesired side effects; PA1 prolonged and constant buspirone plasma concentrations over 24 hours which will avoid underdosing between dosage intervals; PA1 a therapeutically useful increase in the plasma level ratio of unchanged buspirone relative to the metabolite 1-PP; PA1 a significant increase of the relative extent of buspirone bioavailability (i.e. the therapeutically relevant component); PA1 much higher tolerability of the drug, i.e. much less side effects; PA1 a once daily dosing of buspirone which together with the higher tolerability will increase patient compliance. PA1 Polymers: synthetic polymers of polyvinyl type, e.g. poly vinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, polyvinylpyrrolidone. PA1 Polyethylene type, e.g. polyethylene, polystyrene. PA1 Polymers of acrylic acid or acrylic acid ester type, e.g. methylmethacrylate or copolymers of acrylic monomers. PA1 Biopolymers or modified biopolymers of cellulose, e.g. ethylcellulose, cellulose acetate phthalate, cellulose acetate, hydroxy propyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, Na-carboxymethyl cellulose; sodium alginate; chitosan. PA1 Shellac PA1 Gelatin PA1 Fats, oils, higher fatty acids and higher alcohols e.g. aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated vegetable oil, hydrogenated castor oil, 12-hydroxystaryl alcohol, glyceryl mono- or dipalmitate, glyceryl mono- di-, or tristearate, myristyl alcohol, stearic acid, stearyl alcohol. PA1 Polyethyleneglycols PA1 Waxes e.g. bees wax, carnauba wax, Japan wax, paraffin, spermaceti, synthetic wax. PA1 Sugars and sugar alcohols e.g. mannitol, sorbitol, sucrose, xylitol, glucose, maltose.
Buspirone, an azaspirondecanedione, with the structural formula ##STR1##
Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl]-8-azaspiro(4,5)-decane-7,9-dio ne (disclosed in U.S. Pat. No. 3,717,634) is a pharmaceutically active compound which has been found to be effective for the treatment of anxiety disorders and depression. However, buspirone shows a very high first pass metabolism and only about 4% of a therapeutic dose will reach the systemic circulation unchanged after oral administration (Mayol et al., Clin Pharmacol. Ther., 37, 210, 1985). Great interindividual variations in buspirone absorption have also been observed as demonstrated by variations of the maximum plasma concentration of drug by up to 10-fold (Gammans et al., American J. Med., 80, Suppl. 3B, 41-51, 1986). Metabolites have been identified, including several hydroxylated derivatives of buspirone that show little pharmacological activity and the major metabolite; 1-(2-pyrimidinyl)piperazine, (1-PP), which has been found in its own right to be about 20-25% as potent an anxiolytic agent as buspirone in pharmacologic testing.
The biological half-life of buspirone is very short and variable in man, on an order of 2-11 hours, whereas the much less active metabolite, 1-PP, has much slower elimination (Mayol et al., Clin Pharmacol. Ther., 37, 210, 1985). These pharmacokinetic properties necessitate a rather frequent daily dosing regimen which would be expected to have a negative effect on patient compliance. Since buspirone is rapidly absorbed after an oral dose, high peak plasma values occur shortly after drug administration and these are associated with the occurrence of undesired or adverse events observed during the first days of treatment. These adverse effects can also seriously impact patient compliance due to resultant deliberate disruption of the drug therapy. Since its clinical introduction, buspirone has suffered from a perceived lack of immediate effect and much of this may be attributable to patient compliance. Patient monitoring evidences inappropriate dosing--either using buspirone as a night-time dose or taking it prn.
An initial object of this invention was to provide for administration oral controlled/extended release dosage forms of buspirone wherein desirable pharmacologic blood levels, i.e. not too high or too low, of the pharmacologically active component (unmetabolized buspirone) were maintained in the patient's systemic circulation. Such a pharmacokinetic profile contrasts with that following administration of conventional immediate release tablets where initial high peak plasma concentrations of buspirone (with adverse effects) and rapid elimination were experienced. The object then was to be able to increase the time intervals between drug dosing while retaining effectiveness and yet improve drug tolerability at the same time.
Because buspirone has complicated pharmacokinetics with extensive first pass metabolism, attempts to modify buspirone oral absorption, e.g. to simplify the daily dosing without the risk of underdosing between each time of administration, by means of an extended release delivery system which would minimize undesired side effects; had never been undertaken.
It is well known to one skilled in the art that extensive or complex metabolism of a drug makes the design of an oral controlled/extended release product very difficult. It has been shown in the literature that reductions in systemic availability due to metabolism during the absorptive process can be greater for controlled/extended release drug dosage forms than for immediate release drug products. Hence, it has been claimed that drugs which undergo extensive first pass clearance are unsuitable for oral controlled/extended release dosing (J. R. Robinson and V. H. L. Lee, Controlled Drug Delivery: Fundamentals and Applications, Marcel Dekker Inc., USA, 1987, ISBN 0-8247-7588-0). It has also been shown in the literature that metabolism of a drug, e.g. alprenolol, was more complete when it was administered in a controlled/extended release form than in conventional tablets (R. Johansson, C. G. Reg.ang.rdh and J. Sjogren, Acta Pharm, Suec., 8, 59 (1971)). Many other similar examples have been reviewed in the literature (J. R. Robinson and V. H. L. Lee, Controlled Drug Delivery: Fundamentals and Applications, Marcel Dekker Inc., USA, 1987, ISBN 0-8247-7588-0).
With these pharmacokinetic disclosures and the variable extensive oral metabolism of buspirone, it was not apparent that a desirable pharmacokinetic profile could be obtained by development of oral extended-release formulations of buspirone. It was completely unexpected that not only was the bioavailability of buspirone increased but, in addition, the ratio of buspirone to 1-PP plasma levels would be significantly increased due to lower plasma levels of 1-PP that result following administration of controlled/extended release oral formulations of buspirone.